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Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J


Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells1. Proteins that bind specific phosphoinositides mediate interactions between membrane-bounded compartments whose identity is partially encoded by cytoplasmic phospholipid tags. Little is known about the localization and regulation of mammalian phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a phospholipid present in small quantities that regulates membrane trafficking in the endosome–lysosome axis in yeast2. Here we describe a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy and diluted pigmentation in the ‘pale tremor’ mouse. Positional cloning identified insertion of ETn2β (early transposon 2β)3 into intron 18 of Fig4 (A530089I17Rik), the homologue of a yeast SAC (suppressor of actin) domain PtdIns(3,5)P2 5-phosphatase located in the vacuolar membrane. The abnormal concentration of PtdIns(3,5)P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome–lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia is followed by loss of neurons from layers four and five of the cortex, deep cerebellar nuclei and other localized brain regions. The sciatic nerve exhibits reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity and reduced amplitude of compound muscle action potentials. We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot–Marie–Tooth disorder is designated CMT4J.

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Figure 1: Phenotypes of homozygous pale tremor mice.
Figure 2: Neuropathology in pale tremor mice.
Figure 3: Pathological abnormalities in peripheral nerves.
Figure 4: Mutations of FIG4 in patients with CMT disorder.
Figure 5: Yeast Fig4 Ile > Thr is defective in activation of kinase Fab1/PIKfyve.


  1. 1

    Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Michell, R. H., Heath, V. L., Lemmon, M. A. & Dove, S. K. Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem. Sci. 31, 52–63 (2006)

    CAS  Article  Google Scholar 

  3. 3

    Maksakova, I. A. et al. Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet. 2, e2 (2006)

    Article  Google Scholar 

  4. 4

    Hughes, W. E., Cooke, F. T. & Parker, P. J. Sac phosphatase domain proteins. Biochem. J. 350, 337–352 (2000)

    CAS  Article  Google Scholar 

  5. 5

    Duex, J. E., Tang, F. & Weisman, L. S. The Vac14p–Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover. J. Cell Biol. 172, 693–704 (2006)

    CAS  Article  Google Scholar 

  6. 6

    Rudge, S. A., Anderson, D. M. & Emr, S. D. Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14–Fig4 complex, a PtdIns(3,5)P2-specific phosphatase. Mol. Biol. Cell 15, 24–36 (2004)

    CAS  Article  Google Scholar 

  7. 7

    Duex, J. E., Nau, J. J., Kauffman, E. J. & Weisman, L. S. Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels. Eukaryot. Cell 5, 723–731 (2006)

    CAS  Article  Google Scholar 

  8. 8

    Bonangelino, C. J. et al. Osmotic stress-induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p. J. Cell Biol. 156, 1015–1028 (2002)

    CAS  Article  Google Scholar 

  9. 9

    Gary, J. D. et al. Regulation of Fab1 phosphatidylinositol 3-phosphate 5-kinase pathway by Vac7 protein and Fig4, a polyphosphoinositide phosphatase family member. Mol. Biol. Cell 13, 1238–1251 (2002)

    CAS  Article  Google Scholar 

  10. 10

    Rutherford, A. C. et al. The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport. J. Cell Sci. 119, 3944–3957 (2006)

    CAS  Article  Google Scholar 

  11. 11

    Marks, M. S. & Seabra, M. C. The melanosome: membrane dynamics in black and white. Nature Rev. Mol. Cell Biol. 2, 738–748 (2001)

    CAS  Article  Google Scholar 

  12. 12

    Schroder, J. M. Neuropathology of Charcot–Marie–Tooth and related disorders. Neuromolecular Med. 8, 23–42 (2006)

    Article  Google Scholar 

  13. 13

    Szigeti, K., Garcia, C. A. & Lupski, J. R. Charcot–Marie–Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genet. Med. 8, 86–92 (2006)

    Article  Google Scholar 

  14. 14

    Begley, M. J. et al. Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proc. Natl Acad. Sci. USA 103, 927–932 (2006)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Bolino, A. et al. Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis. J. Cell Biol. 167, 711–721 (2004)

    CAS  Article  Google Scholar 

  16. 16

    Bolino, A. et al. Charcot–Marie–Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nature Genet. 25, 17–19 (2000)

    CAS  Article  Google Scholar 

  17. 17

    Bonneick, S. et al. An animal model for Charcot–Marie–Tooth disease type 4B1. Hum. Mol. Genet. 14, 3685–3695 (2005)

    CAS  Article  Google Scholar 

  18. 18

    Senderek, J. et al. Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot–Marie–Tooth neuropathy type 4B2/11p15. Hum. Mol. Genet. 12, 349–356 (2003)

    CAS  Article  Google Scholar 

  19. 19

    Stendel, C. et al. Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, frabin/FGD4. Am. J. Hum. Genet. (in the press); preprint at (2007)

  20. 20

    Verhoeven, K. et al. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot–Marie–Tooth type 2B neuropathy. Am. J. Hum. Genet. 72, 722–727 (2003)

    CAS  Article  Google Scholar 

  21. 21

    Zuchner, S. et al. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot–Marie–Tooth disease. Nature Genet. 37, 289–294 (2005)

    Article  Google Scholar 

  22. 22

    Schmitt-John, T. et al. Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse. Nature Genet. 37, 1213–1215 (2005)

    CAS  Article  Google Scholar 

  23. 23

    Park, M. et al. Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52, 817–830 (2006)

    CAS  Article  Google Scholar 

  24. 24

    Adamska, M., Billi, A. C., Cheek, S. & Meisler, M. H. Genetic interaction between Wnt7a and Lrp6 during patterning of dorsal and posterior structures of the mouse limb. Dev. Dyn. 233, 368–372 (2005)

    Article  Google Scholar 

  25. 25

    Escayg, A. et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genet. 24, 343–345 (2000)

    CAS  Article  Google Scholar 

  26. 26

    Rainier, S., Sher, C., Reish, O., Thomas, D. & Fink, J. K. De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Arch. Neurol. 63, 445–447 (2006)

    Article  Google Scholar 

  27. 27

    Li, J. et al. Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration. J. Comp. Neurol. 498, 252–265 (2006)

    CAS  Article  Google Scholar 

  28. 28

    Kohrman, D. C., Harris, J. B. & Meisler, M. H. Mutation detection in the med and medJ alleles of the sodium channel Scn8a. Unusual splicing due to a minor class AT–AC intron. J. Biol. Chem. 271, 17576–17581 (1996)

    CAS  Article  Google Scholar 

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For discussions and advice we are grateful to A. Dlugosz, E. Feldman, D. Goldowitz, J. Hammond, L. Isom, J. M. Jones, A. Lieberman, M. Khajavi, J. Swanson, K. Verhey and S. H. Yang. S. Cheek and M. Hancock provided technical assistance. This research was supported by NIH research grants (M.H.M., L.W. and J.R.L.) and NIH predoctoral training (C.Y.C.).

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Correspondence to Miriam H. Meisler.

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Supplementary information

Supplementary Information 1

This file contains Supplementary Video Legend, Supplementary Figures 1-10 with Legends and Supplementary Discussion. (PDF 4003 kb)

Supplementary Information 2

This file contains Supplementary Video 1 which shows the typical movement disorder of the plt mouse. The mouse is four weeks old. (MOV 2031 kb)

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Chow, C., Zhang, Y., Dowling, J. et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448, 68–72 (2007).

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